A drug costing 5 cents could help us live longer, healthier lives.
Used for decades to treat type 2 diabetes, metformin is showing promise as an anti-ageing drug. Researchers are looking into whether metformin holds
the key to living longer — and the latest research has been favourable.
Metformin Has a Long History
What we know today as metformin, has a long history. It is the active ingredient in a plant known as French lilac or goat’s rue. Doctors have been prescribing
it as an herbal remedy for centuries. Goat’s rue has been used since medieval times as a remedy for frequent urination, a tell-tale sign of diabetes. French physician
Jean Sterne isolated the active compound from the French lilac in the 1950s. Today, we know that compound as metformin.
Metformin was introduced as a medication in France in 1957 and was approved by the FDA for treating type 2 diabetes in 1994, and in other countries decades
earlier. While the drug is primarily used to fight the epidemic of type 2 diabetes, it is used for other conditions, as well. The inexpensive generic is also used
off-label to treat other conditions like gestational diabetes, prediabetes, and polycystic ovarian disease. A growing body of evidence shows that the drug prevents
cancer, heart disease, and type 2 diabetes.
Using metformin as an anti-ageing drug makes sense since it helps the body use insulin properly, lowering blood sugar. Metformin decreases glucose production
in the liver, decreases intestinal absorption of glucose, and improves insulin sensitivity. Because metformin effectively lowers both blood sugar and insulin levels,
it also reduces the risk of many other chronic degenerative diseases. Metformin also promotes weight loss.
Evidence on Metformin’s Anti-Ageing Properties
The evidence on metformin and anti-ageing has come from observational studies. The FDA doesn’t believe ageing is a disease. Nor are they convinced by the
observational studies that metformin can slow down ageing in the general population. To convince the FDA to consider ageing as a treatable disease, researchers
are a conducting a landmark clinical trial called Treating Ageing with Metformin(TAME). The goal of TAME is to prove that both metformin and anti-ageing
drugs are topics worth further investment.
Advocate for Metformin and Anti-Ageing
Nir Barzilai, MD is the leading spokesperson for metformin and anti-ageing science in general. Dr. Barzilai knows a thing or two about ageing, as he is currently
director of the Institute for Ageing Research at the Albert Einstein College of Medicine. Dr. Barzilai is an expert on the genetics of ageing, metformin and
Wired reporter Sam Apple caught up with Dr. Barzilai and asked him about metformin and anti-ageing in July of this year. After talking to Dr. Barzilai and other
anti-ageing researchers, the correspondent summarized the powers of metformin:
“The metformin-takers tended to be healthier in all sorts of ways. They lived longer and had fewer cardiovascular events, and in at least some studies they were
less likely to suffer from dementia and Alzheimer’s.”
“Most surprising of all, they seemed to get cancer far less frequently—as much as 25 to 40 percent less than diabetics taking two other popular medications.
When they did get cancer, they tended to outlive diabetics with cancer who were taking other medications.” – Sam Apple
Barzilai’s Obsession with Metformin and Anti-Ageing
Nir Barzilai, MD, has received acclaim for his work on metformin and anti-ageing in general. He has been featured in a National Geographic documentary on ageing,
and in the Wall Street Journal, CNN.com, the New York Times, and the Washington Post.
Early in his career, Dr. Barzilai conducted a series of studies on centenarians, people who live to an unusually old age. The doctor discovered that centenarians
died from the same chronic diseases as everyone else, but they developed them the at ends of their lives. In other words, they somehow managed to slow the
ageing process and compress the diseases of ageing into their last years. Dr. Barzilai drew blood samples from hundreds of centenarians and studied their genetic
code to find out what made them live longer than most. The researcher discovered anti-ageing genes. Barzilai hopes to use the discovery as a basis for an
anti-ageing medicine for the general population. Until then, metformin is the leading anti-ageing candidate and a favourite subject of Dr. Barzilai.
Metformin in Longevity Study (MILES)
Dr. Barzilai is an expert on metformin and its anti-ageing properties. The researcher first studied the diabetes medicine in the late 1980’s while completing a
fellowship at Yale University. Dr. Barzilai conducted an earlier study called the Metformin in Longevity Study (MILES). MILES was a pilot study that examined
metformin’s anti-ageing effects in older adults with prediabetes.
The MILES team wanted to see if metformin could restore the ageing genes of older prediabetics to those of young healthy subjects. The researchers divided
he study participants into two groups. They gave the test subjects 1700 milligrams of metformin daily and gave the others placebo. Barzilai’s team has already
completed the MILES study, and are currently analysing the results.
Taming Ageing with Metformin (TAME)
Dr. Barzilai again entered the spotlight when he spearheaded the Taming Ageing with Metformin (TAME) study, the world’s first clinical trial for an anti-ageing drug.
The Food and Drug Administration (FDA) has given the go ahead for TAME, a double-blind, placebo-controlled study.
Dr. Barzilai gave an interview in 2015 to Healthspan Campaign in which he expressed his excitement about metformin and its anti-ageing powers.
The researcher cited evidence that metformin delays the onset of many diseases of ageing, including heart disease, cancer, and premature death.
As reported in the interview, TAME is the first test of an anti-ageing drug. During the interview, Dr. Barzilai said TAME is a randomized controlled trial testing
metformin’s anti-ageing abilities on 3,000 healthy, nondiabetic seniors. The study participants will be followed for five years to test whether metformin can
delay the chronic diseases of ageing including cancer, cardiovascular disease, type 2 diabetes, cognitive decline, and premature death.
Barzilai has two expectations for the TAME study. First, for the FDA to accept ageing as a treatable condition. Second, to demonstrate that metformin is a
bonafide anti-ageing drug. The TAME trial is a proof of concept which will show that both metformin and anti-ageing medicines merit further attention.
While metformin may not be the strongest anti-ageing elixir, if the FDA approves it as a way to combat old age, it will pave the way for other anti-ageing
Barzilai’s Essay On Metformin and Anti-Ageing
In a 2016 essay in the journal Cell, Dr. Barzilai made a compelling case for metformin and anti-ageing drugs. The respected researcher cited evidence showing
that metformin prevents heart disease, diabetes, cancer and Alzheimer’s disease.
Citing as evidence, Barzilai referred to a massive observational study, the 2014 Bannister Study on metformin use. The landmark study got the attention of
many in the medical and anti-ageing community when it showed that, on average, type 2 diabetics taking metformin lived about the same number of years as
people without diabetes.
An amazing result, because type 2 diabetics usually die ten years earlier than normal people. Even more remarkable was the finding that the older metformin-treated
participants – those over the age of 70 – lived longer their matched non-diabetic control group. The authors of the Bannister study also suggested that metformin
may help ordinary people – those without diabetes – to live longer.
Before they can develop anti-ageing drugs, scientists must first understand the complex ageing process. Scientists believe there are many pathways involved in ageing.
As well there are anti-ageing pathways that block the process. Once scientists have identified the exact ageing pathways, they can develop drugs that block them.
Several anti-ageing pathways have already been identified. Known anti-ageing interventions include changes in diet, such as fruit and vegetables, exercise and
medications, including metformin. While they have made great progress, anti-ageing researchers have not reached a consensus on exactly how humans age.
Metformin’s Anti-Ageing Mechanisms
While the evidence shows that metformin has anti-ageing properties, no one has identified the exact mechanisms of action. The molecular mechanisms underlying
metformin’s mode of action are complicated and remain a topic of debate. The molecular pathways affected by metformin and anti-ageing mechanisms are complex
and intersect at several points. While scientists understand which pathways metformin effects; they do not fully understand how the drug impacts ageing.
hey know that autophagy, inflammation, and cellular senescence all cause ageing, but they are not quite sure how to block them.
Metformin and Anti-Ageing Effects On Blood Chemistry
As we grow older, we gain weight, and our blood sugar, insulin, cholesterol, and triglycerides levels rise. Metformin reverses these conditions. Metformin inhibits
the production of glucose in the liver. This enables the pancreas to reduce the production of insulin which results in lower levels of blood glucose and insulin.
Metformin increases insulin sensitivity, meaning the body uses insulin more efficiently. Metformin also decreases appetite and food consumption, causing weight loss.
The anti-ageing drug also decreases triglycerides and LDL-cholesterol levels.
Metformin and Anti-Ageing Effects On Insulin
Excess insulin is damaging and is one cause of accelerated ageing. Excess insulin causes damage to virtually all organs in the body, especially the kidneys, eyes,
nerves, and blood vessels. Elevated insulin levels are incredibly pro-ageing, they increase blood pressure, obesity, chronic inflammation, atherosclerosis, and
Alzheimer’s disease. By lowering insulin levels, metformin reduces the incidence of these diseases.
Metformin’s Anti-Ageing Effects On Blood Sugar
Sugar sometimes combines with proteins, rendering them non-functional. The process is called glycosylation and produces advanced glycation end-products
(AGEs) which have been linked to ill health. Because metformin lowers blood sugar levels, it reduces glycosylation and slows down the destruction of
proteins throughout the body. Metformin is truly an anti-ageing wonder.
In his essay Barzilai notes metformin’s anti-ageing properties, writing:
“Metformin favourably influences metabolic and cellular processes closely associated with the development of age-related conditions, such as inflammation,
autophagy and cellular senescence.”
“Specifically for ageing, metformin leads to decreased insulin levels, decreased IGF-1 signalling, inhibition of mTOR, inhibition of mitochondrial complex 1
in the electron transport chain, and reduction of endogenous production of reactive oxygen species (ROS) activation of AMP-activated kinase (AMPK),
and reduction in DNA damage.”
Metformin Reduces Heart Disease
In his essay, Barzilai showed that metformin prevents heart disease in type 2 diabetics. Dr. Barzilai cited evidence shown by the 1998 United Kingdom
Prospective Diabetes Study (UKPDS). The UKPDS study compared metformin to other diabetes medications. Compared to other diabetes medications,
he diabetics taking metformin had a reduced risk of all diabetes-related complications, including heart attack, stroke, and death.
After the UKPDS trial ended in 1998, the original participants were followed for another ten years. In 2008, the UKPDS team reported that metformin
continued to work well since 1998, reducing all diabetes complications by 21%, including reducing the risk of heart attack by 33%, diabetes-related death
by 30%, and lowering the risk of all causes of death by 27%.
Since 2008, metformin’s ability to prevent cardiovascular disease has also been confirmed by many other authors. Substantial evidence has built up over the
years, based on research studies using human subjects, including the meta-analysis by Lamanna in 2011, as well as studies by lead authors Johnson (2005),
Roumie (2012) and Hong (2013).
Metformin Stalls Diabetes
Studies of prediabetics taking metformin have shown that the drug prevents type 2 diabetes. Prediabetes is a precursor to diabetes, a condition in which
a person has high blood sugar, but is not yet diabetic.
With a healthy diet and exercise, type 2 diabetes can be delayed or prevented. Overweight people are at risk of developing the disease unless they take steps
to prevent it.
Metformin has been extensively studied as a prediabetes treatment. An extensive study called the Diabetes Prevention Program (DPP) showed that diet and
exercise sharply reduced the odds that a prediabetic would develop type 2 diabetes. Metformin also reduced the risk, although less dramatically.
A related article provides more detail about metformin as a prediabetes treatment. Metformin is not yet fully approved for the prevention of diabetes in prediabetics.
The use of metformin in prediabetics is considered an acceptable off-label use by the U.S. FDA. Only a few countries, such as Poland, Turkey, and The Philippines,
fully accept the practice.
Metformin Reduces Cancer Rates
In 2014, Gandini and colleagues published the strongest evidence to date that metformin prevents cancer. Up until that time, the evidence had been piling up,
with dozens of studies linking metformin to reduced cancer rates. The Gandini team gathered all the evidence presented by 47 high-quality studies on the subject.
The team pooled the results of the different studies in a massive collation effort called a systematic review, that covered more than 65,000 cancer cases in diabetics.
After aver ageing the results of the various studies, Gandini and colleagues showed that metformin usage reduced the rate of cancer by 31% and mortality by 34%.
A related article discusses how metformin prevents cancer in people with health conditions. A bit of caution is advised, although the evidence is strong, to
date, all the research linking metformin with cancer has only been observational. Additionally, metformin has been shown to reduce cancer in type 2 diabetics,
not in healthy people.
Other Viewpoints On Metformin and Anti-Ageing
The naysayers point to the fact that metformin has not been tested in healthy people. While studies have shown that metformin prevents age-related diseases in
diabetics, it has not been shown to work in healthy non-diabetics.
Take Home Message
- Researchers aren’t sure if metformin will have the same anti-ageing effects in non-diabetics. For confirmation, we have to wait for the results of the TAME and MILES trials.
- Studies of type 2 diabetics and pre-diabetics show that metformin has many health benefits. Metformin use helps prevent diabetes in prediabetics. As well, studies show that type 2 diabetics using metformin have reduced rates of cancer and heart disease. The health benefits of metformin make it the world’s most popular type 2 diabetes medicine.